Terminal duct lobular unit involution of the normal breast: Implications for breast cancer etiology

Terminal duct lobular units (TDLUs) are the structures within the breast that produce milk and the primary source of most breast cancer precursors and cancers (Figure 1) (1). With completion of childbearing and physiological aging, TDLUs involute, resulting in a reduction in acini (substructures) number/TDLU and total TDLU counts (2–3). The determinants of age-related TDLU involution are undefined, and understanding these processes may elucidate factors associated with persistence of acini and TDLUs in later life, and elevated breast cancer risk (3). Analysis of women who have undergone a breast biopsy, which showed benign breast disease (BBD), suggests that those who have less TDLU involution are more likely to develop breast cancer than those with greater degrees of involution, extending findings in rodent models linking mammary development, microanatomy, and cancer susceptibility (3–11). Figure 1. Terminal duct lobular unit (TDLU) involution assessment in the Susan G. Komen Tissue Bank. Three quantitative measures (TDLU count, TDLU span, and number of acini per TDLU) associated with reduced levels of TDLU involution were assessed from digitized ... Standardized, reproducible quantitative measurements to evaluate TDLU involution have not been developed. An analysis of benign biopsies from 8756 women in the Mayo BBD Cohort found that the absence of TDLU involution, based on subjective assessment, was associated with a statistically significant increase in breast cancer risk (relative risk [RR] = 1.88, 95% CI = 1.59 to 2.21) compared with the general population (8). Additional analyses in this cohort demonstrated that increased acini counts/TDLU or TDLU area were related to increased five-year risk independent of Gail model risk prediction (7). Using an adaptation of a TDLU involution classification developed in rodent models (11), the Nurses’ Health Study II demonstrated a 29% reduction in cancer risk among women with BBD containing predominantly type 1 lobules (fewer than 12 acini) and lacking type 3 lobules (approximately 80 acini) (4). To date, studies of TDLU involution have been limited by a lack of access to large collections of epidemiologically annotated normal breast samples that were obtained for research as opposed to clinical diagnosis (3,12). The Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center (KTB) addresses these limitations by providing a resource of normal breast tissues, risk factor data, and blood from volunteers for research (13–14). Given that the best method for assessing the level of TDLU involution is unknown, we performed morphometric assessment of TDLUs and developed three reproducible quantitative measures that are inversely associated with TDLU involution, TDLU counts per standardized biopsy, median acini counts/TDLU, and median TDLU span, in order to identify factors associated with TDLU involution in normal breast tissues from the KTB.